The dopamine D4 receptor plays an important role in regulating functions of prefrontal cortex (PFC), a brain region critically involved in cognitive an emotional processes. A unique feature of human D4 receptor (hD4R) gene is the existence of a large number of polymorphisms in exon 3 that codes for the third intracellular loop, which consists of a variable number (2-11) of tandem repeats. Human D4R variants with long repeats have been associated with deficiencies in executive control processes in Attention Deficit and Hyperactivity Disorder (ADHD) and schizophrenia. The goal of this application is to understand the molecular and physiological basis of the polymorphism of human D4 receptors. Combined approaches will be used to test the hypothesis that hD4R variants regulate PFC glutamatergic transmission and network activity differentially by interacting with different proteins and activating distinct signaling pathways, which contributes to their different roles in mental health and disorders. Using D4R knockout mice with in vivo viral infection of hD4R variants and human D4.7R (ADHD-linked variant containing 7 repeats) knockin mice, we will reveal the impact of different human D4R variants on NMDAR trafficking and function and AMPAR-mediated synaptic transmission in PFC pyramidal neurons. Moreover, we will assess the effects of human D4R variants on synchronized network bursts, which originate from the large scale correlated activity of interconnected neurons and control selective attention. This study will significantly advance our understanding on the synaptic functions of human D4R variants and their role in mental disorders. The combined use of cutting-edge techniques enables us to effectively test the functional role of human D4R polymorphism in PFC circuits.